Human lipoxygenases (LOXs) are the enzymes participating in the metabolism of the polyunsaturated fatty acids and catalyzing their oxidation to a variety of eicosanoids, which as the secondary signal transducers have a major impact on human homeostasis. They are involved in many diseases such as inflammatory responses, cancers, cardiovascular and kidney diseases, neurodegenerative disorders and metabolic syndrome[1].PD146176 (NSC168807), a 15-Lipoxygenase (15-LO) inhibitor, inhibits rabbit reticulocyte 15-LO (Ki=197 nM, IC50=0.54 μM). PD146176 reverses cognitive impairment, brain amyloidosis, and tau pathology by stimulating autophagy in aged triple transgenic mice[2]. In intact IC21 cells transfected with human 15-LO, PD146176 inhibits 13-HODE production with an IC50 of 0.81 μM[3]. PD146176 (80 mg/kg; Chowing; 12 weeks) reverses cognitive impairment, brain amyloidosis, and Tau pathology by stimulating autophagy in aged triple transgenic mice[4]. Compared with mice receiving placebo, the group treated with PD146176 manifested a significant improvement of their memory deficits. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a decrease in the β-secretase pathway. In addition, while total tau-soluble levels were unchanged for both groups, PD146176-treated mice had a significant reduction in its phosphorylation state and insoluble fraction, which specifically associated with decrease in stress-activated protein kinase/c-Jun N-terminal kinase activity[5].
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